By Debby Hamilton, MD, MPH

Introduction

Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS) has had multiple names and criteria over the years since it was first described in 1988.  It was originally called chronic fatigue syndrome alone.  The prevalence has ranged depending on the case definition criteria used. With the commonly used CDC case definition in 1994, the prevalence of ME/CFS is approximately 0.895%.¹   There are two to three times as many women as men impacted with this disorder.  Up to twenty other diagnostic criteria have been developed, including the Canadian Criteria updated in 2011-2012 to the International Consensus Criteria.²

To make a diagnosis of ME/CFS the person has to have self-reported persistent or relapsing fatigue lasting at least six consecutive months, the absence of other fatigue-related conditions and other minor symptoms.²  One of the distinguishing factors in the fatigue is called post-exertional malaise where minor physical or cognitive efforts result in profound fatigue. Other common symptoms include muscle aches, joint pains, sleep disturbance, cognitive dysfunction, and headaches.² People often have disturbances in autonomic function, neuroendocrine issues, and immune system regulation. The symptoms of autonomic dysfunction include dizziness and fainting when standing up, abnormal heart rate variability, slow digestion, abnormal sweating, urinary and visual issues resulting in the diagnosis of postural orthostatic tachycardia syndrome (POTS) in some patients.^3,4

The prognosis for ME/CFS varies with the initial severity of symptoms.⁵ People with more severe onset tend to have a poorer recovery.  Most patients tend to report an improvement in symptoms versus a full recovery.⁶ Although ME/CFS is not a fatal disease, unless associated with other co-existing illness, it is disabling for many people. Approximately one-quarter of people with the disease are considered disabled and unable to work.⁷

Pathological Risk Factors

No one definitive cause has been found to cause all cases of ME/CFS.  It appears to arise from a multi-factorial combination of environmental factors.  Many people with ME/CFS report an infection preceding the development of their symptoms.  There is research showing a range of pathology with this disease from infections to immune dysregulation to mitochondrial dysfunction.⁸  As with most chronic diseases, there are multiple factors that probably cause a cascade effect leading to the vast range of signs and symptoms in ME/CFS. It also appears that there may be subsets of the disease with different factors playing a causative role.

Mitochondrial Dysfunction in ME/CFS

Fatigue is one of the primary symptoms in ME/CFS and is a primary symptom seen in mitochondrial disease.  Therefore, mitochondrial dysfunction biologically makes sense as an important factor involved in the development of the disease.  Other common symptoms such as muscle pain, weakness, and cognitive dysfunction can also be explained by mitochondrial dysfunction.⁹   Classical mitochondrial disease from genetic causes will exhibit similar symptoms but is often diagnosed earlier in life and has multiple organ involvement such as cardiac and kidney disease.¹⁰ Mitochondrial metabolism creates cellular energy for the body in the form of ATP. This energy production requires multiple cofactors that if low could decrease the production of ATP. There are multiple steps in the development of energy beginning with the breakdown of the macronutrients: lipids, carbohydrates, and protein.  Because of this, there are many places where dysfunction can happen in the mitochondria. 

A decrease in mitochondrial number has been found in research using muscle biopsies.¹¹ The decrease can be as severe as people with ME/CFS having half the normal number of mitochondria.¹¹  If there are less mitochondria, then muscles would have less ability to have full force of contraction and would potentially tire more easily.  A decreased number of mitochondria is trying to do the same amount of work as a normal number of mitochondria. The formation of cellular energy in the form of ATP creates free radicals.  An increased attempt to produce energy may create more free radicals leading to an increase in oxidative stress.  An increase in oxidative stress then creates more damage to cell membranes further harming the mitochondria.

Structural changes in the mitochondria leading to decreased function have been observed in several studies.^12,13  One of the first studies of mitochondrial structure found differences in shape and size of these organelles from skeletal muscle biopsies.¹²   The cristae of the mitochondria showed branching and fusion thought to arise from the increased energy needs.^12,13

The mitochondria produce ATP through a process called oxidative phosphorylation.  This happens through the electron transport chain, which is one of the last steps in energy formation and takes place in the mitochondrial membrane.  In people with ME/CFS, there is a decrease in mitochondrial energy production because of depressed oxidative phosphorylation.^14,15  In a study by Tomas, he compared people with ME/CFS versus controls on seven key parameters of oxidative phosphorylation, including basal respiration, ATP production, maximal respiration, proton leak, reserve capacity, non-mitochondrial respiration, and coupling efficiency.¹⁴  Multiple parameters differed between the two groups, but the difference in maximal respiration was the largest.¹⁴ Ultimately, this leads to lower amounts of ATP production resulting in a lower reserve capacity to produce energy.¹⁴  Without adequate ATP production people with ME/CFS are unable to meet their increased energy needs such as with exercise.

The electron transport chain has complexes I-V, which are critical for forming ATP.  In genetic mitochondrial syndromes there can be a defect in individual complexes leading to fatigue and other mitochondrial issues often diagnosed in childhood.  With ME/CFS, research has looked for differences in the levels of complexes compared to controls.  One study by Missailidis found a defect in complex V, which is ATP synthase.¹⁶ Other research failed to find any differences in Complexes I-IV, although there was still a decrease in oxidative phosphorylation and consequently ATP production.¹³ This suggests another factor impacting this metabolic process of energy formation such as oxidative stress.

Oxidative stress results from an excess of free radicals and an inadequate number of antioxidants. Mitochondria produce free radicals as part of the normal production of ATP, making them the primary producer in the cell.⁹ Because of this, mitochondria are also at high risk from free radical damage, which can impact their DNA and their cell membrane. Within the mitochondria, there are antioxidants such as vitamin E and CoQ10 which can prevent damage from free radicals. Multiple studies have shown increased markers of oxidative stress in ME/CFS patients causing damage to the mitochondria, inflammation, and brain dysfunction.^17,18  Increased oxidative stress has been found post-exercise and in relapse of patients with ME/CFS.^17,19

Since antioxidants are important to combat oxidative stress, a decrease in antioxidants can be associated with a higher level of free radicals.    A decrease in the antioxidant CoQ10 has been associated with an increase in free radicals and mitochondrial damage.²⁰  Patients with ME/CFS have lower levels of CoQ10 in their mitochondria.¹⁹  Carnitine is another marker of mitochondrial function that has been studied in ME/CFS.  Dysfunctional levels of carnitine were found in all studies of ME/CFS that were investigating this nutrient.²¹

Testing for Mitochondrial Function

Since mitochondrial dysfunction appears to be a factor in ME/CFS, it is important for both researchers and practitioners to be able to diagnose this issue.  Measuring mitochondrial function in research has found the ATP profile test to cover a full range of mitochondrial energy metabolism.²² The ATP profile test was designed to study ME/CFS and other fatigue illnesses.²³   This profile has five factors used to obtain a mitochondrial energy score.²³  These factors include the availability of ATP in cells, the efficiency of oxidative phosphorylation, the portion of ATP complexed with magnesium, the efficiency that ADP is transferred into the mitochondria, and ATP is transferred into the cytosol.²³   Research initially found a high degree of correlation between the degree of mitochondrial dysfunction measured with the ATP profile test and the severity of the fatigue.²³  Subsequent research did not substantiate the test and found no difference between groups.¹⁴ Other markers used in research include the measurement of mitochondrial proteins and oxygen consumption using live plated cells.⁹

Clinical testing has focused on specific blood markers and urine testing.  These include a complete metabolic panel, lactate, pyruvate, ammonia, creatine kinase, amino acids, total and free carnitine and acylcarnitine profile.  A functional medicine organic acid test can also be extremely helpful. My experience as a practitioner is that the functional medicine organic test shows markers for mitochondrial dysfunction before the development of abnormal blood markers. With increased severity and duration of mitochondrial dysfunction, I am more likely to see elevated blood markers.

When mitochondrial disease is suspected, the traditional diagnosis is from a muscle biopsy. Genetic testing is also done in mitochondrial disease to check for specific genetic mitochondrial syndromes such as Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like Episodes (MELAS).  Recently a cheek swab genetic test called Mitoswab was developed to evaluate complexes I through IV of the electron transport chain and is easily accessible for patients and practitioners. Mitoswab can be helpful for mitochondrial disease and mitochondrial dysfunction in terms of targeting nutrient support such as CoQ10 involved in the electron transport chain.

Oxidative stress with an excess of free radicals is a factor in the development of mitochondrial dysfunction.  A panel of both biomarkers for oxidative stress and antioxidants was compared between people with chronic fatigue and healthy volunteers.²⁴ People with chronic fatigue had elevated oxidative markers such as reactive oxygen species, malondialdehyde (MDA), F2-isoprotane, and TNF-alpha.²⁴   This correlated with a decrease in antioxidant markers such as total antioxidant activity, catalase, superoxide dismutase, and SOD and GSH in people with chronic fatigue.²⁴  In practice, commonly available markers are F2-isoprotanes, markers of lipid peroxidation, and 8-hydroxy-2′ -deoxyguanosine (8-OHdG), marker of mitochondrial and other DNA damage.  Elevated levels of both of these oxidative stress markers have been found in patients with ME/CFS.^25,26

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